Fig. 6: Chemogenetic inhibition of STN neurons restores motor function in a mouse model of advanced PD.

a, Timeline for the virus injection, drug treatments and behavioral tests in MitoPark and littermate control mice. b, Schematic illustration of bilateral viral delivery of AAV5-hSyn-hM4D(Gi)-mCherry or AAV5-hSyn-mCherry to the STN of MitoPark and littermate control mice. c, Representative image to show the expression of hM4D(Gi)-mCherry in the STN of a MitoPark mouse. Scale bar, 200 μm. d, DAB staining of TH⁺ cells in the ventral midbrain and TH⁺ terminals in the striatum. Scale bars, 500 µm for midbrain and 1 mm for the striatum. e,f, Quantification of the number of TH⁺ neurons in the SNc (e) and the TH⁺ terminal optical density in the striatum (f) in 29-week-old MitoPark and littermate control mice. ****P < 0.0001 (for e, P < 0.0001; for f, P < 0.0001), unpaired two-tailed t-test. n = 5 mice for littermate control, n = 7 mice for MitoPark mice, including both males and females. g−j, Open field (g,i) and rotarod (h,j) tests in littermate control and MitoPark mice expressing hM4D(Gi)-mCherry or mCherry in the STN, measured longitudinally at the ages of 25 weeks (g,h) and 29 weeks (i,j). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (for g: Littermate-mCherry-Vehicle versus MitoPark-mCherry-Vehicle, P < 0.0001; MitoPark-mCherry-CNO-0.5 h versus MitoPark-Gi-CNO-0.5 h, P= 0.0008; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-0.5 h, P = 0.0023; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-5 h, P = 0.0144; for h: Littermate-mCherry-Vehicle versus MitoPark-mCherry-Vehicle, P < 0.0001; MitoPark-mCherry-CNO-0.5 h versus MitoPark-Gi-CNO-0.5 h, P < 0.0001; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-0.5 h, P < 0.0001; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-5 h, P < 0.0001; for i: Littermate-mCherry-Vehicle versus MitoPark-mCherry-Vehicle, P < 0.0001; MitoPark-mCherry-CNO-0.5 h versus MitoPark-Gi-CNO-0.5 h, P = 0.0002; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-0.5 h, P = 0.0007; for j: Littermate-mCherry-Vehicle versus MitoPark-mCherry-Vehicle, P < 0.0001; MitoPark-mCherry-CNO-0.5 h versus MitoPark-Gi-CNO-0.5 h, P < 0.0001; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-0.5 h, P < 0.0001; MitoPark-Gi-Vehicle versus MitoPark-Gi-CNO-5 h, P = 0.0009), two-way ANOVA followed by Tukey’s multiple comparisons test. All data are plotted as mean ± s.e.m. n = 9 mice for littermate control + mCherry group; n = 9 mice for littermate control + Gi-DREADD group; n = 12 mice for MitoPark + mCherry group; n = 12 mice for MitoPark + Gi-DREADD group, including both males and females. See Supplementary Video 5 for representative behavior videos. i.p., intraperitoneal.

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